This chapter focuses on routes of carbon metabolism and nitrogen metabolism, on specific aspects of their regulation, and on insights specifically gained for Aspergillus fumigatus, by far the most pathogenic species among aspergilli and the main causative agent of aspergillosis. Fungi contribute significantly to the global recycling routes that result in turnover of elements like carbon or nitrogen, and aspergilli with their saprophytic life-style inhabit a prominent role in these processes. Genomic data from several Aspergillus species, among them A. fumigatus, have not revealed the existence of true virulence factors that would cause significant host damage; in fact, they clearly mirror the routine of degrading external polymers and assimilation of nutrients. Signal transduction pathways affecting the fungal response to varying environmental conditions are likely to contribute to its nutritional versatility, and identification of nutritional pathways supporting growth of Aspergillus in the ecological niche of a ‘‘susceptible host’’ could provide the capability to pinpoint fungus-specific virulence determinants and therefore targets of antifungal therapy. This is of course not limited to routes of carbon metabolism. The chapter also discusses the accumulated knowledge of nitrogen metabolism of A. fumigatus with respect to its pathogenicity.

Metabolism as a virulence determinant of Aspergillus. This scheme illustrates the pathogen-host interaction as a variation of Aspergillus exploiting a specific environment. After infection by airborne conidia, the surrounding tissue has to be utilized to allow germination and hyphal growth, which eventually may result in a final outcome of disease. Nutritional versatility occupies a crucial role in this setting and therefore affects the aftermath of the pathogen-host encounter.

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Figure 1.

Metabolism as a virulence determinant of Aspergillus. This scheme illustrates the pathogen-host interaction as a variation of Aspergillus exploiting a specific environment. After infection by airborne conidia, the surrounding tissue has to be utilized to allow germination and hyphal growth, which eventually may result in a final outcome of disease. Nutritional versatility occupies a crucial role in this setting and therefore affects the aftermath of the pathogen-host encounter.

Routes of carbon metabolism to utilize fatty acids and amino acids. Various metabolic pathways are used by Aspergillus in utilizing carbon sources, including fatty acids and amino acids. (A) The former result in increased levels of acetyl-CoA and anaplerosis of the tricarbonic cycle (TCC) intermediate oxaloacetate via the glyoxalate bypass. The intermediate glyoxalate is formed by the action of an isocitrate lyase enzyme (AcuD; EC 4.1.3.1), which is dispensable in invasive aspergillosis (Schöbel et al., 2007). (B) The methylcitrate cycle feeds from propionyl-CoA, which derives from isoleucine, valine, or methionine as products from protein degradation. Its condensation with the TCC intermediate oxaloacetate is catalyzed by methylcitrate synthetase activity (McsA; EC 6.2.1.17), an enzyme that is essential for invasive aspergillosis (Ibrahim-Granet et al., 2008). Accordingly, A. fumigatus appears to utilize amino acids as a source for carbon and nitrogen.

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Figure 2.

Routes of carbon metabolism to utilize fatty acids and amino acids. Various metabolic pathways are used by Aspergillus in utilizing carbon sources, including fatty acids and amino acids. (A) The former result in increased levels of acetyl-CoA and anaplerosis of the tricarbonic cycle (TCC) intermediate oxaloacetate via the glyoxalate bypass. The intermediate glyoxalate is formed by the action of an isocitrate lyase enzyme (AcuD; EC 4.1.3.1), which is dispensable in invasive aspergillosis (Schöbel et al., 2007). (B) The methylcitrate cycle feeds from propionyl-CoA, which derives from isoleucine, valine, or methionine as products from protein degradation. Its condensation with the TCC intermediate oxaloacetate is catalyzed by methylcitrate synthetase activity (McsA; EC 6.2.1.17), an enzyme that is essential for invasive aspergillosis (Ibrahim-Granet et al., 2008). Accordingly, A. fumigatus appears to utilize amino acids as a source for carbon and nitrogen.

Cross-pathway control signaling in Aspergillus. The schematic outline shows the core components and regulatory effects in the eIF2α kinase signaling cascade of fungal cross-pathway control. Nutritional stress, such as amino acid starvation, is perceived by the kinase CpcC, which in turn phosphorylates the α-subunit of eIF2. This results in lower rates of translation initiation but elevated expression of the transcription factor CpcA, mediated by two uORFs on the cpcA transcript. Accordingly, transcriptional reprogramming occurs to counter the initial stress condition. The presence of the cpcA gene is required for full virulence of A. fumigatus (Krappmann et al., 2002), whereas a cpcCΔ deletant is as virulent as wild type (Sasse et al., 2008).

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Figure 3.

Cross-pathway control signaling in Aspergillus. The schematic outline shows the core components and regulatory effects in the eIF2α kinase signaling cascade of fungal cross-pathway control. Nutritional stress, such as amino acid starvation, is perceived by the kinase CpcC, which in turn phosphorylates the α-subunit of eIF2. This results in lower rates of translation initiation but elevated expression of the transcription factor CpcA, mediated by two uORFs on the cpcA transcript. Accordingly, transcriptional reprogramming occurs to counter the initial stress condition. The presence of the cpcA gene is required for full virulence of A. fumigatus (Krappmann et al., 2002), whereas a cpcCΔ deletant is as virulent as wild type (Sasse et al., 2008).

Aspects of primary carbon and nitrogen metabolism that influence pathogenicity of Aspergillus. Several biosynthetic routes have been identified as required for aspergillosis, and a variety of regulatory circuits have been analyzed in this respect, too. However, distinct aspects of basic C or N metabolism have been scrutinized only to a limited extent, and the role of nutritional transporters has not been addressed thoroughly. See text for further details.

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Figure 4.

Aspects of primary carbon and nitrogen metabolism that influence pathogenicity of Aspergillus. Several biosynthetic routes have been identified as required for aspergillosis, and a variety of regulatory circuits have been analyzed in this respect, too. However, distinct aspects of basic C or N metabolism have been scrutinized only to a limited extent, and the role of nutritional transporters has not been addressed thoroughly. See text for further details.

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45. Liebmann,B.,, S.Gattung,, B.Jahn, and, A. A.Brakhage.2003.cAMP signaling in Aspergillus fumigatus is involved in the regulation of the virulence gene pksP and in defense against killing by macrophages.Mol. Genet. Genomics269:420–435.